MikeFit_NJ said:I want to add the drug interaction perspective on the pharmacology.
Semaglutide structural biology relevant to the pharmacology: semaglutide is a 31-amino acid peptide with 94% homology to native GLP-1(7-36). Three key modifications enable its pharmacokinetic profile:
- Aib8 substitution: DPP-4 resistance (prevents enzymatic degradation)
- Arg34 substitution: improved chemical stability
- C18 fatty diacid at Lys26: albumin binding → long half-life
These three modifications transform a peptide with a 2-minute half-life (native GLP-1) into one with a 168-hour half-life (semaglutide). A masterclass in peptide engineering.
BenResearch_OR said:I went looking for why the dosing schedule is what it is and found that almost every practical question on this board has a pharmacokinetic answer…
Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%), creating a depot effect with a ~168-hour half-life enabling weekly dosing[1].
Tirzepatide is a dual GIP/GLP-1R agonist with higher GIP affinity (5:1 GIP:GLP-1 potency ratio). The GIP component may enhance beta-cell function and adipocyte lipid metabolism beyond what GLP-1 alone achieves.
For the pharmacology, the pharmacology explains the clinical differences between these agents.
[1] Lau J, et al. J Med Chem. 2015;58(18):7370-7380.
Dr.ObesityMed said:Semaglutide structural biology relevant to the pharmacology: semaglutide is a 31-amino acid peptide with 94% homology to native GLP-1(7-36).
Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest trajectory ever seen for an anti-obesity agent[1].
Amylin receptor agonism enhances satiety signaling through the area postrema and reduces glucagon secretion. Combined with GLP-1R agonism, this dual mechanism may produce even greater efficacy than current agents.
Early-stage data — interpret with caution. But the trajectory is extraordinary.
[1] Novo Nordisk investor presentation, September 2023.
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Shop Reference StandardsOne thing that is still open after anna.melb_AU’s answer:
Was that from a primary source or from a summary of one?
OP back with an update, since a thread like this is useless without one.
Closing this out: the trough rather than the peak explains the pattern I was seeing on day six, which I had been blaming on the vial.